Nuclear Lipid Microdomains Regulate Daunorubicin Resistance in Hepatoma Cells
Daunorubicin is an anticancer drug, and cholesterol is involved in cancer progression, but their relationship has not been defined. In this study, we developed a novel experimental model that utilizes daunorubicin, cholesterol, and daunorubicin plus cholesterol in the same cells (H35) to search for...
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doaj-43363dd20a5f462caec7ab2e1cca9c292020-11-25T02:11:16ZengMDPI AGInternational Journal of Molecular Sciences1422-00672018-11-011911342410.3390/ijms19113424ijms19113424Nuclear Lipid Microdomains Regulate Daunorubicin Resistance in Hepatoma CellsMichela Codini0Carmela Conte1Samuela Cataldi2Cataldo Arcuri3Andrea Lazzarini4Maria Rachele Ceccarini5Federica Patria6Alessandro Floridi7Carmen Mecca8Francesco Saverio Ambesi-Impiombato9Tommaso Beccari10Francesco Curcio11Elisabetta Albi12Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, ItalyDepartment of Experimental Medicine, University of Perugia, 06126 Perugia, ItalyLaboratory of Nuclear Lipid BioPathology, CRABiON, 06122 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, ItalyLaboratory of Nuclear Lipid BioPathology, CRABiON, 06122 Perugia, ItalyDepartment of Experimental Medicine, University of Perugia, 06126 Perugia, ItalyDipartimento di Area Medica, University of Udine, 33100 Udine, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, ItalyDipartimento di Area Medica, University of Udine, 33100 Udine, ItalyDepartment of Experimental Medicine, University of Perugia, 06126 Perugia, ItalyDaunorubicin is an anticancer drug, and cholesterol is involved in cancer progression, but their relationship has not been defined. In this study, we developed a novel experimental model that utilizes daunorubicin, cholesterol, and daunorubicin plus cholesterol in the same cells (H35) to search for the role of nuclear lipid microdomains, rich in cholesterol and sphingomyelin, in drug resistance. We find that the daunorubicin induces perturbation of nuclear lipid microdomains, localized in the inner nuclear membrane, where active chromatin is anchored. As changes of sphingomyelin species in nuclear lipid microdomains depend on neutral sphingomyelinase activity, we extended our studies to investigate whether the enzyme is modulated by daunorubicin. Indeed the drug stimulated the sphingomyelinase activity that induced reduction of saturated long chain fatty acid sphingomyelin species in nuclear lipid microdomains. Incubation of untreated-drug cells with high levels of cholesterol resulted in the inhibition of sphingomyelinase activity with increased saturated fatty acid sphingomyelin species. In daunodubicin-treated cells, incubation with cholesterol reversed the action of the drug by acting via neutral sphingomyelinase. In conclusion, we suggest that cholesterol and sphingomyelin-forming nuclear lipid microdomains are involved in the drug resistance.https://www.mdpi.com/1422-0067/19/11/3424sphingomyelincholesterolnuclear membranenuclear lipid microdomainsdaunorubicin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Michela Codini Carmela Conte Samuela Cataldi Cataldo Arcuri Andrea Lazzarini Maria Rachele Ceccarini Federica Patria Alessandro Floridi Carmen Mecca Francesco Saverio Ambesi-Impiombato Tommaso Beccari Francesco Curcio Elisabetta Albi |
spellingShingle |
Michela Codini Carmela Conte Samuela Cataldi Cataldo Arcuri Andrea Lazzarini Maria Rachele Ceccarini Federica Patria Alessandro Floridi Carmen Mecca Francesco Saverio Ambesi-Impiombato Tommaso Beccari Francesco Curcio Elisabetta Albi Nuclear Lipid Microdomains Regulate Daunorubicin Resistance in Hepatoma Cells International Journal of Molecular Sciences sphingomyelin cholesterol nuclear membrane nuclear lipid microdomains daunorubicin |
author_facet |
Michela Codini Carmela Conte Samuela Cataldi Cataldo Arcuri Andrea Lazzarini Maria Rachele Ceccarini Federica Patria Alessandro Floridi Carmen Mecca Francesco Saverio Ambesi-Impiombato Tommaso Beccari Francesco Curcio Elisabetta Albi |
author_sort |
Michela Codini |
title |
Nuclear Lipid Microdomains Regulate Daunorubicin Resistance in Hepatoma Cells |
title_short |
Nuclear Lipid Microdomains Regulate Daunorubicin Resistance in Hepatoma Cells |
title_full |
Nuclear Lipid Microdomains Regulate Daunorubicin Resistance in Hepatoma Cells |
title_fullStr |
Nuclear Lipid Microdomains Regulate Daunorubicin Resistance in Hepatoma Cells |
title_full_unstemmed |
Nuclear Lipid Microdomains Regulate Daunorubicin Resistance in Hepatoma Cells |
title_sort |
nuclear lipid microdomains regulate daunorubicin resistance in hepatoma cells |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2018-11-01 |
description |
Daunorubicin is an anticancer drug, and cholesterol is involved in cancer progression, but their relationship has not been defined. In this study, we developed a novel experimental model that utilizes daunorubicin, cholesterol, and daunorubicin plus cholesterol in the same cells (H35) to search for the role of nuclear lipid microdomains, rich in cholesterol and sphingomyelin, in drug resistance. We find that the daunorubicin induces perturbation of nuclear lipid microdomains, localized in the inner nuclear membrane, where active chromatin is anchored. As changes of sphingomyelin species in nuclear lipid microdomains depend on neutral sphingomyelinase activity, we extended our studies to investigate whether the enzyme is modulated by daunorubicin. Indeed the drug stimulated the sphingomyelinase activity that induced reduction of saturated long chain fatty acid sphingomyelin species in nuclear lipid microdomains. Incubation of untreated-drug cells with high levels of cholesterol resulted in the inhibition of sphingomyelinase activity with increased saturated fatty acid sphingomyelin species. In daunodubicin-treated cells, incubation with cholesterol reversed the action of the drug by acting via neutral sphingomyelinase. In conclusion, we suggest that cholesterol and sphingomyelin-forming nuclear lipid microdomains are involved in the drug resistance. |
topic |
sphingomyelin cholesterol nuclear membrane nuclear lipid microdomains daunorubicin |
url |
https://www.mdpi.com/1422-0067/19/11/3424 |
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